Hedgehog induces a gut reaction

Tian et al. reveal how Hedgehog (Hh) signaling prompts intestinal stem cells to proliferate in response to injury.

Just like in mammalian intestines, cells in the Drosophila midgut constantly turn over and are replaced by intestinal stem cells (ISCs), which divide to produce enteroblasts that subsequently differentiate into more specialized cell types. ISC proliferation is up-regulated upon intestinal injury, and Tian et al. found that Hh signaling drove this response, even though the pathway was not required for normal, homeostatic ISC proliferation.

Feeding flies with the detergent DSS damaged their guts and, via the JNK signaling pathway, induced production of the Hh ligand. Surprisingly, Hh didn’t drive ISC proliferation by acting directly on the stem cells themselves. Instead, Hh prompted enteroblasts to up-regulate the cytokine Upd2, which stimulated ISC proliferation by activating the JAK–STAT signaling pathway. Knocking down Upd2 or inhibiting the Hh pathway in enteroblasts suppressed DSS-induced ISC proliferation.

Senior author Jin Jiang now wants to determine whether Upd2 is a direct transcriptional target of the Hh pathway and to investigate whether there is any crosstalk with the Hippo pathway, which also regulates ISC proliferation in response to intestinal injury.